The Human Immunodeficiency Virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. Subsequent to the introduction of combination antiretroviral therapy (ART), HIV-infection-related morbidity and mortality have dramatically decreased; however, currently available antiretroviral agents, such as those involved in highly active antiretroviral therapy (HAART), are only capable of controlling HIV replication, rather than completely eradicating virus from patients. As a result, HIV infection has now become a chronic disease requiring a lifelong commitment to daily oral treatment.
HAART comprises complex regimens that require strict adherence to complicated treatment schedules, and the quality of treatment depends on the patient's adherence to the recommended regimens. Antiretroviral adherence is the second strongest predictor of progression to AIDS and death, after CD4 count (Garcia de Olalla, P. et al., J Acquir Immune Defic Syndr. 2002; 30(1):105-110; Nowacek, A. et al., Nanomedicine (Lond). 2009; 4(5):557-574).
Currently HAART only helps in suppressing HIV replication and does not clear virus from infected individuals. Various reservoirs of replication-competent HIV have been identified that may contribute to this persistence.
Most antiretroviral drugs have a short half-life and, in turn, need to be in circulation constantly to control the virus replication. As a result, it is believed that missing a medication dose even once can provide an opportunity for viruses to replicate such that a medication-resistant HIV strain may develop.
Long-acting formulations of therapeutic agents have been used to improve adherence and prevent issues such as missing doses or treatment fatigue to prescribed medication in a number of different fields such as contraception, male hypogonadism, and schizophrenia, with demonstrable success (Boffito, M. et al., Drugs. 2014; 74(1):7-13). Thus, it has been suggested that development of similar approaches in reducing the impact of individual adherence could increase the efficacy of treatment strategies for HIV-AIDS.
Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) being used as part of HAART for the treatment of HIV-1. Although it is always given in combination with other drugs to treat HIV infection, the low efficacy is still a main concern for this drug. The low efficacy is due to its poor aqueous solubility, low bioavailability, and resistance profile.
The gastrointestinal tract plays a key role in not only early HIV infection in establishing viral reservoirs in gut-associated lymphoid tissue (GALT) but also disease pathology. The epithelium that lines the human gut is impermeable to macromolecules/microorganisms except Peyer's patches, where the follicle-associated epithelium contains microfold cells (M-cells). M-cells are specialized epithelial cells that are predominantly present in the GALT Many pathogenic organisms exploit M-cells to cross the digestive epithelial barrier10.
Many different treatment options have been proposed to eradicate the virus from GALT; however, due to the complex physiology involved, it is difficult to design drugs that are targeted toward GALT.
Therefore, the identification of means to improve the bioavailability and therapeutic index of HAART drugs to eradicate the GALT reservoir is of great importance.